Tumor Biology

, Volume 36, Issue 11, pp 8637–8643 | Cite as

Application of chemokine receptor antagonist with stents reduces local inflammation and suppresses cancer growth

  • Ai-Wu Mao
  • Ting-Hui Jiang
  • Xian-Jun Sun
  • Jian Peng
Research Article


Severe pain and obstructive jaundice resulting from invasive cholangiocarcinoma or pancreatic carcinoma can be alleviated by implantation of biliary and duodenal stents. However, stents may cause local inflammation to have an adverse effect on the patients’ condition and survival. So far, no efficient approaches have been applied to prevent the occurrence of stents-related inflammation. Here, we reported significantly higher levels of serum stromal cell-derived factor 1 (SDF-1) in the patients that developed stents-associated inflammation. A higher number of inflammatory cells have been detected in the cancer close to stent in the patients with high serum SDF-1. Since chemokine plays a pivotal role in the development of inflammation, we implanted an Alzet osmotic pump with the stents to gradually release AMD3100, a specific inhibitor binding of SDF-1 and its receptor C-X-C chemokine receptor 4 (CXCR4), at the site of stents in mice that had developed pancreatic cancer. We found that AMD3100 significantly reduced local inflammation and significantly inhibited cancer cell growth, resulting in improved survival of the mice that bore cancer. Moreover, the suppression of cancer growth may be conducted through modulation of CyclinD1, p21, and p27 in the cancer cells. Together, these data suggest that inhibition of chemokine signaling at the site of stents may substantially improve survival through suppression of stent-related inflammation and tumor growth.


Pancreatic cancer Stents Inflammation Stromal cell-derived factor 1 (SDF-1) 


Conflicts of interest



  1. 1.
    Srinivasan I, Kahaleh M. Biliary stents in the millennium. Adv Ther. 2011;28:960–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Deviere J. Pancreatic stents. Gastrointest Endosc Clin N Am. 2011;21:499–510.CrossRefPubMedGoogle Scholar
  3. 3.
    Gupta R, Reddy DN. Stent selection for both biliary and pancreatic strictures caused by chronic pancreatitis: multiple plastic stents or metallic stents? J Hepatobiliary Pancreat Sci. 2011;18:636–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Choudhary A, Bechtold ML, Arif M, Szary NM, Puli SR, Othman MO, et al. Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review. Gastrointest Endosc. 2011;73:275–82.CrossRefPubMedGoogle Scholar
  5. 5.
    Thotakura RV, Thotakura S, Sofi A, Bawany MZ, Nawras A. Synchronous EUS-guided choledochoduodenostomy with metallic biliary and duodenal stents placement in a patient with malignant papillary tumor. J Intervent Gastroenterol. 2012;2:88–90.CrossRefGoogle Scholar
  6. 6.
    Hamada T, Isayama H, Nakai Y, Togawa O, Kogure H, Kawakubo K, et al. Duodenal invasion is a risk factor for the early dysfunction of biliary metal stents in unresectable pancreatic cancer. Gastrointest Endosc. 2011;74:548–55.CrossRefPubMedGoogle Scholar
  7. 7.
    Katsinelos P, Kountouras J, Germanidis G, Paroutoglou G, Paikos D, Lazaraki G, et al. Sequential or simultaneous placement of self-expandable metallic stents for palliation of malignant biliary and duodenal obstruction due to unresectable pancreatic head carcinoma. Surg Laparosc Endosc Percutan Tech. 2010;20:410–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11:762–74.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30:245–57.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Tettamanti G, Malagoli D, Benelli R, Albini A, Grimaldi A, Perletti G, et al. Growth factors and chemokines: a comparative functional approach between invertebrates and vertebrates. Curr Med Chem. 2006;13:2737–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Ruiz de Almodovar C, Luttun A, Carmeliet P. An SDF-1 trap for myeloid cells stimulates angiogenesis. Cell. 2006;124:18–21.CrossRefPubMedGoogle Scholar
  13. 13.
    Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell. 2006;124:175–89.CrossRefPubMedGoogle Scholar
  14. 14.
    Cao X, Han ZB, Zhao H, Liu Q. Transplantation of mesenchymal stem cells recruits trophic macrophages to induce pancreatic beta cell regeneration in diabetic mice. Int J Biochem Cell Biol. 2014;53:372–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Lieber M, Mazzetta J, Nelson-Rees W, Kaplan M, Todaro G. Establishment of a continuous tumor-cell line (PANC-1) from a human carcinoma of the exocrine pancreas. Int J Cancer. 1975;15:741–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Khan IF, Hirata RK, Russell DW. AAV-mediated gene targeting methods for human cells. Nat Protoc. 2011;6:482–501.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Grieger JC, Choi VW, Samulski RJ. Production and characterization of adeno-associated viral vectors. Nat Protoc. 2006;1:1412–28.CrossRefPubMedGoogle Scholar
  18. 18.
    Koerber JT, Maheshri N, Kaspar BK, Schaffer DV. Construction of diverse adeno-associated viral libraries for directed evolution of enhanced gene delivery vehicles. Nat Protoc. 2006;1:701–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Zhu HD, Guo JH, Mao AW, Lv WF, Ji JS, Wang WH, et al. Conventional stents versus stents loaded with (125)iodine seeds for the treatment of unresectable oesophageal cancer: a multicentre, randomised phase 3 trial. Lancet Oncol. 2014;15:612–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Li T, Zhao X, Mo Z, Huang W, Yan H, Ling Z, et al. Formononetin promotes cell cycle arrest via downregulation of Akt/Cyclin D1/CDK4 in human prostate cancer cells. Cell Physiol Biochem. 2014;34:1351–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Yan X, Shen H, Jiang H, Hu D, Wang J, Wu X. External Qi of Yan Xin Qigong inhibits activation of Akt, Erk1/2 and NF-κB and induces cell cycle arrest and apoptosis in colorectal cancer cells. Cell Physiol Biochem. 2013;31:113–22.CrossRefPubMedGoogle Scholar
  22. 22.
    Wu X, Yang N, Zhou WH, Xu J, Chen JJ, Zheng FM, et al. Up-regulation of P21 inhibits TRAIL-mediated extrinsic apoptosis, contributing resistance to SAHA in acute myeloid leukemia cells. Cell Physiol Biochem. 2014;34:506–18.CrossRefPubMedGoogle Scholar
  23. 23.
    Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.CrossRefPubMedGoogle Scholar
  24. 24.
    Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008;8:327–36.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A. 2014;111:E1211–20.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344:921–5.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Xu H, Sun Y, Zhang Y, Wang W, Dan J, Yao J, et al. Protoporphyrin IX induces a necrotic cell death in human THP-1 macrophages through activation of reactive oxygen species/c-Jun N-terminal protein kinase pathway and opening of mitochondrial permeability transition pore. Cell Physiol Biochem. 2014;34:1835–48.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang W, Tian J, Hao Q. HMGB1 combining with tumor-associated macrophages enhanced lymphangiogenesis in human epithelial ovarian cancer. Tumour Biol. 2014;35:2175–86.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Ai-Wu Mao
    • 1
    • 2
  • Ting-Hui Jiang
    • 1
    • 2
  • Xian-Jun Sun
    • 2
  • Jian Peng
    • 1
  1. 1.Xiangya Hospital of Central South UniversityChangshaChina
  2. 2.Interventional CenterSt. Luke’s Hospital of Jiaotong University School of MedicineShanghaiChina

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